My research interests are focused on the mechanisms of nuclear receptor regulation of glucose metabolism, with long-term goals of broadening our understanding of how resistance in insulin-sensitive tissues integrates with whole body glucose homeostasis, and lead to the development of novel therapeutic targets. To this end, I have spent the past two years of my Pediatric Endocrinology Fellowship training in the laboratory of Dr. Peter Tontonoz at UCLA, studying the effect of orphan nuclear receptor Nur77 on muscle glucose metabolism. Nur77 has been identified as a transcriptional regulator of hepatic gluconeogenesis. Its role in skeletal muscle, however, was unknown. Recently I demonstrated that Nur77 regulates the expression of a program of glucose utilization genes in both in vitro and in vivo systems. To test the hypothesis that muscle expression of Nur77 regulates muscle function and systemic glucose metabolism, I will utilize both loss-of-function and gain-of-function mouse models in my studies. Aim 1 tests how Nur77 expression affects muscle metabolism and function, by determining muscle fiber-type composition and exercise capacity. Aim 2 examines the effect of Nur77 on systemic glucose homeostasis and energy metabolism, by studying insulin sensitivity, body composition, and metabolic rates of the different Nur77 mouse models. The results of these studies will establish the importance of muscle Nur77 expression in physiologic regulation of glucose metabolism, and potentially uncover novel regulatory pathways of glucose metabolism for pharmacologic targeting in the treatment of insulin resistance and diabetes. The data generated in the 3-year award period will also set the stage for my future endeavors to identify signaling pathways that modulate Nur77 activity. Furthermore, these studies will provide the preliminary data to compete for my first R01 grant and establish myself as an independent investigator. In summary, the research program proposed here will further our understanding of the metabolic pathways that regulate glucose homeostasis. At this time of global obesity epidemic, identification of novel pathways that can lead to therapeutic development toward the treatment of insulin resistance and diabetes will have tremendous impact on public health.